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Respiratory syncytial virus (RSV) is the leading cause for childhood hospitalization and respiratory distress, being recognized as a major health and economic burden worldwide. RSV can exploit host immunity and cause a strong inflammatory response that leads to lung damage and virus dissemination. Unfortunately, the immune response elicited by RSV normally fails to protect against subsequent exposures to the virus. Despite intense research during the 50 years after the discovery of RSV, scientists are just beginning to understand the mechanisms contributing to pathology and to the inadequate immune response shown by susceptible individuals. Here, we discuss some of the most important advances made in this field that could lead to the development of new prophylactic tools. Copyright © 2012 John Wiley & Sons, Ltd.

Abbreviations used

Bacille Calmette Guérin


dendritic cell


formalin-inactivated RSV preparation


immunological synapses


myeloid dendritic cells


plasmacytoid dendritic cells


regulatory T cells


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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and young children in the world, as well of infant hospitalization due to respiratory disease. In the USA alone, RSV causes approximately 125 000 annual hospitalizations [1]. Because of the high infectivity of the virus, nearly 70% of children are infected by the age of 1 year, whereas almost 100% have been exposed to the virus during their second year of life. Importantly, about 36% of infants under 2 years have suffered at least two infections [2, 3]. Although infection rates for RSV are similar throughout the world, severe pathology predominantly occurs in infants displaying risk factors, such as incomplete airway development due to premature birth, pulmonary hypertension, airway hyper-reactivity, congenital heart disease and immunosuppression [4]. Furthermore, RSV-associated acute lower respiratory infection and RSV-associated fatality ratios are higher in infants residing in developing countries [5].

Respiratory syncytial virus belongs to the Paramyxoviridae family, which also includes measles, parainfluenza 3, Hendra and Nipah viruses. Together with the recently identified human metapneumovirus, RSV is more specifically classified into the subfamily Pneumovirinae [6]. RSV is an enveloped virus with 10 genes distributed along 15.2 kilobases of negative-stranded RNA that encode 11 proteins (Figure 1). Eight of the RSV proteins are known to be structural and so present in the virion particle (Figure 1). The two non-structural proteins, NS1 and NS2, are expressed only during cell infection and are not packaged into the virion. Whether the M2 gene product, M2-2, is packaged within the virion remains to be determined.


Figure 1. Structure of the respiratory syncytial virus (RSV) virion. RSV is an enveloped virus with eight known structural proteins. The fusion protein (F), the attachment glycoprotein (G) and the small hydrophobic protein (SH) are located on the surface of the virion. The ssRNA genome and the remaining viral structural proteins, which are the matrix (M), the nucleocapsid (N), the RNA-dependent RNA polymerase (L), the phosphoprotein (P) and the M2 gene product M2-1, reside inside the envelope. The exact location of the M2 gene product M2-2 is currently unknown

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Despite extensive research efforts, no vaccines are currently available that are capable of inducing long-lasting protective immunity against this virus. Nevertheless, although a widely used prophylactic strategy based on a humanized neutralizing antibody has been shown to be effective at preventing RSV-induced damage, its high cost has limited the use of this treatment only for high-risk groups, such as preterm infants (<37 weeks of gestational age) and infants suffering from cardiovascular diseases and immunosuppression. Further, the only available antiviral drug for treating RSV replication, ribavirin, has shown questionable cost-effectiveness [7]. Thus, it is essential to generate new treatments or ideally a vaccine for RSV that could be affordable by public health systems worldwide. Such an effort will require a better understanding of the pathology caused by RSV and its effects on the host immune system.

In this review, we discuss the latest findings in the field of RSV infection, pathology and virulence that underscore the complexity of the immune response triggered by this pathogen. Furthermore, we describe new experimental strategies to prevent the pathology induced by the exposure to RSV early in life.


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Protective immunity to respiratory syncytial virus and respiratory syncytial virus-induced immunopathogenesis

In most healthy adults, symptoms elicited after RSV infection manifest as rhinitis, and the course of the disease resembles a common cold. However, RSV can cause severe inflammation of the respiratory tract in susceptible young children, the elderly and immunosuppressed individuals [5, 8, 9]. Further, in some susceptible patients, RSV may also produce damage in other tissues besides the lungs, such as the brain, heart and liver [10-12]. It has been estimated that between 0.5% and 3% of children younger than 2 years manifest severe respiratory symptoms after infection with RSV. Considering that RSV infects ~100% of infants by age 2 years, this apparently small percentage becomes very significant [2, 3]. Similar to other respiratory viruses, RSV can repeatedly re-infect the host, with a significant percentage of children re-infected during their second year of life [2, 3, 13]. However, in most cases the severity of the pathology produced by RSV is gradually reduced after re-infection, diminishing significantly with the age of exposure [2, 3]. Although numerous studies have shown an inverse correlation between the presence of neutralizing antibodies and re-infection [14, 15], several other reports suggest that antibodies developed against RSV during natural infection contribute poorly to protection [16, 17]. Lack of antibody-mediated protection could be due to the fact that RSV-blocking antibodies are usually elicited at very low frequencies after infection, requiring in some cases decades of repetitive exposure to the virus for their acquisition [16-18]. A possible explanation for this phenomenon is the poor immunogenicity of viral protein domains required for virulence. Additionally, other viral proteins are produced in large amounts, such as the secreted form of the G attachment glycoprotein, which could work as an antibody decoy promoting the production of ineffective antibodies to irrelevant viral epitopes (Figure 1) [19]. Thus, because of the absence of effective neutralizing antibodies, it is likely that RSV infection is mainly cleared by IFN-γ secreting CD8+ and CD4+ T cells that promote virus clearance either directly by destroying infected cells or indirectly by limiting inflammation in the lungs [20-25]. Indeed, healthy individuals display T-cell activation levels that are sufficient to mediate viral clearance from the lungs, which promotes low levels of inflammation and hence reduced tissue pathology. The requirement of T-cell immunity for RSV clearance is underscored by the observation that HIV-1-infected patients display increased RSV titres for up to 199 days and mice depleted of CD4+ and CD8+ T cells display prolonged RSV replication [25, 26]. A recent report suggests that the ratio of CD4+/CD8+ RSV-specific T cells may be key to defining the outcome of infection, with higher CD4+/CD8+ memory T cell ratios prevailing in the blood of healthy adults, as compared with those suffering primary RSV infection [27]. Such a finding may be useful in the future to predict disease outcome and assess the potential of experimental vaccines in animal models [28].

Unlike healthy adults, more susceptible hosts can display several harmful immune responses after RSV infection, such as increased inflammation in the lungs, locally impaired or damaging CD8+ T-cell responses and detrimental polarization of CD4+ T cells [24, 29-32]. All these processes are likely to be driven both by viral determinants and host-cell mediators in response to RSV [22, 33]. Recent studies in mice suggest that RSV infection can desensitize alveolar macrophages to TLR ligands for several months after viral resolution [34]. This process could imprint the affected lungs with a phenotype that promotes airway pathology to subsequent viral or bacterial infections [34]. Furthermore, RSV-infected human epithelial cells have been shown to upregulate the expression of inhibitory surface molecules, such as PD-L1 that dampens T-cell activation [35]. Thus, RSV may increase pathology by remodelling the airways [36].

Respiratory syncytial virus interferes with T-cell function

Although RSV antigens are presented and accessible to T cells during infection, as shown by the identification of immunogenic peptides for several RSV proteins in mice and humans, several studies suggest that T-cell function may be specifically impaired in the respiratory tract of those individuals suffering pathology during RSV infection [31, 32, 37, 38]. This notion is supported by the observation that RSV-specific T cells remain functional in the periphery after viral infection, a phenomenon also seen for other respiratory viruses [31, 37, 38]. These findings have led to the concept that impaired antiviral T-cell immune responses in the lungs may be associated with both the tissue itself and the infecting pathogen. Despite this, CD8+ T cells in the lungs of RSV-infected individuals show reduced intracellular granzyme B content, limited secretion of IFN-γ and failure to upregulate perforin expression upon antigen stimulation [31, 38]. All these immune features are required for the destruction of virus-infected cells. It is noteworthy that production of IFN-γ by CD8+ T cells confronted with RSV can be restored by adding exogenous IL-2, a phenomenon also observed for anergic T cells [31]. Consistent with this notion, in vivo IL-2 supplementation can significantly improve the effector function of lung CD8+ T cells recognizing RSV in infected animals [32]. These studies indicate that cytotoxic T cells recognizing RSV display an altered phenotype at the lungs and do not secrete key cytokines, such as IL-2 and IFN-γ, which are required for the activation and full display of antiviral T-cell activity. Although it is tempting to relate reduced T-cell activation by RSV-infected dendritic cells (DCs) with subsequent host re-infections, this concept was recently challenged by respiratory viruses that block T-cell activation without necessarily re-infecting their hosts more frequently [13].

Other studies have shown that, despite controlling virus replication, RSV-induced T cells contribute to pathology because disease severity can be significantly reduced by depleting mice of these cells [25]. Consistent with this notion is the observation that RSV infection in neonate and adult mice can induce virus-specific CD4+ and CD8+ T cells, which are fully activated during infection yet display detrimental phenotypes that enhance disease severity during primary and secondary infection [29, 39, 40].

These observations suggest that RSV has evolved molecular mechanisms to dampen the antiviral T-cell immune response and also to promote in certain cases the induction of unwanted pro-inflammatory T cells.

Respiratory syncytial virus impairs dendritic cell function to modulate T-cell activation

Pathogens can avoid T-cell immunity by dampening the function of DCs [41, 42], which are professional antigen-presenting cells that sense pathogens through the engagement of pattern recognition receptors. Pathogen encounter generally leads to DC maturation and the secretion of immune-stimulating cytokines that contribute to the activation and polarization of T cells [43-45]. Upon exposure to RSV, most human and murine DCs display abortive levels of viral RNA synthesis, and only a fraction of cells become readily infected (Figure 2) [46-50]. Consistently, only negligible numbers of viral particles can be recovered from the supernatants of infected DCs. Thus, evidence suggests that these cells may be exploited by RSV to manipulate immunity rather than for viral replication. In fact, although DCs can recognize RSV molecular patterns via a variety of receptors, such as TLRs and RIG-1 [43, 44], human and murine DCs undergo only weak maturation after virus encounter. Thus, only a modest upregulation of surface activation markers, such as CD40, CD80, CD86 and MHC (Figure 2) [46-49, 51], is observed for DCs after RSV challenge. Nevertheless, DCs respond to the virus by secreting polarizing cytokines, such as IL-6 and IL-10, which can promote T-cell differentiation into phenotypes that are poorly effective at clearing the virus (Figure 2) [47, 51]. Therefore, RSV seems to have developed molecular strategies to interfere with the function of DCs. Accumulating data suggest that in vitro infected human and murine DCs fail to efficiently prime T cells [47-49, 52], probably because of the reduced capacity of RSV-infected DCs to secrete activating cytokines, such as IL-12, required to induce CD4+ T cells capable of driving the expansion of cytotoxic and memory CD8+ T cells (Figure 2) [22, 38, 46, 47, 49, 53, 54]. However, the identification of host and viral molecular determinants that account for the altered response shown by DCs to RSV infection remains elusive. Along these lines, a recent report showed that neonate and adult human DCs secrete different cytokine patterns in response to RSV, especially for the levels of TGF-β produced [55]. Cord blood-derived DCs secreted significantly more TGF-β1 in response to RSV infection than did DCs obtained from adult blood [55]. Furthermore, contrastingly different cytokine profiles were obtained in the co-cultures of these RSV-infected DCs with autologous T cells. Whereas co-cultures with adult DCs contained IL-2, IL-12, IFN-γ and TNF-α, those with cord DCs contained IL-1β, IL-4, IL-6 and IL-17 [55]. This differential response of neonatal and adult DCs to RSV could contribute to increased infant susceptibility to developing inadequate virus-specific T-cell immunity and lung pathology. Consistent with this notion, neutralization of IL-17 in RSV-infected mice was recently shown to significantly reduce the production of mucus in the airways and decrease viral loads in the lungs [56]. Furthermore, IL-17 neutralization led to an increase in the number of RSV-specific CD8+ T cells, thereby reducing the production of Th2 cytokines in RSV-exacerbated allergic mice. In another study, IL-4−/− mice displayed reduced peribronchial lymphocytic inflammation as well as increased levels of the Th1 cytokine IFN-γ [57]. RSV infection leads to a sustained increase in the lung recruitment of both myeloid (mDCs) and plasmacytoid DCs (pDCs) in mice and humans. Further, as a result of infection, migration of these cells to the lymph nodes also takes place [58-62].


Figure 2. Respiratory syncytial virus (RSV) interferes with DC and T-cell function. (1) RSV can infect DCs, as shown by the surface expression of viral encoded proteins, such as the fusion F protein and intracellular expression of viral RNA (nucleocapsid gene). (2) Upon infection with RSV, DCs mature as a result of the engagement of surface and internal pathogen recognition receptors, such as TLRs, lectins and RIG-I by viral determinants. (3) RSV-infected DCs secrete cytokines that can either promote CD4+ T-cell differentiation into Th2 phenotypes (e.g. IL-10 and IL-6) or inhibit their function (e.g. IFN-λ and IFN-α) [49, 53]. Furthermore, infection in neonates may promote the generation of detrimental CD8+ T cells. Additionally, DCs can secrete chemokines, such as CXCL10 and CCL2, that modulate immune cell migration. (4) RSV can impair DC–T cell interaction by interfering with immunological synapse assembly (detailed in Figure 3). (5) The soluble form of the RSV G glycoprotein can interfere with T-cell differentiation and migration by interacting with CX3CR1 receptors expressed on the surface of T cells. (6) Few reports have provided evidence for direct interaction between RSV and T cells at their surface, which has been described to interfere with T-cell cytoskeleton organization in response to activating stimuli. (7) RSV can impair T-cell activation and function in the lungs by reducing IFN-γ secretion. (8) T cells activated in the context of an RSV infection can display Th2 phenotypes and secrete characteristic inflammatory cytokines

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Plasmacytoid DCs accumulating in the lungs of RSV-infected mice secrete IFN-α and other type-I IFNs in response to the virus and are thought to contribute to controlling RSV-mediated lung pathology [59, 63, 64]. On the other hand, DCs subtypes different from plasmacytoid, such as monocyte-derived human DCs, fail to secrete these cytokines in high amounts in response to RSV, which would partly reduce DC maturation [65]. Previous experiments performed on human epithelial cell lines have reported that NS1/2 can interfere with STAT-2 function to modulate NF-κB and IRF-3 activity, leading to altered type-I IFN signalling [66, 67]. A recent report showed that RSV can also interfere with STAT-1 and STAT-2 signalling in murine bone-marrow derived DCs [68]. In fact, NS1 could negatively modulate the capacity of human DCs to activate both CD4+ and CD8+ T cells by decreasing the proliferation of cytotoxic CD8+ T cells that migrate to the lungs and reducing the activation and proliferation of CD4+ Th17 cells with potential antiviral effects [39]. Furthermore, NS1 was seen to promote the capacity of DCs to activate IL-4-secreting CD4+ T cells while reducing the proliferation of total CD4+ T cells. Strikingly, nearly all these effects were shown to be independent of type-I IFN signalling.

Blockade of the chemokine CCL20 during RSV infection in mice reduced the frequency of mDCs in the lungs but did not alter pDC numbers or the recruitment of T cells [69]. Such a treatment ultimately led to reduced lung pathology and an enhanced Th1 effector response against RSV [69]. Similar data were obtained in CCR6−/− animals, which support the notion that pDCs contribute positively to RSV clearance and that CCL20 may enhance this process [59, 69].

Respiratory syncytial virus interferes with dendritic cell–T cell synapse

Another mechanism by which RSV may alter T-cell activation and function is to impair the assembly of productive immunological synapses (IS) between RSV-infected DCs and antigen-specific CD4+ T cells (Figure 3(A)) [47, 70, 71]. Thus, by interfering with IS assembly, RSV could render DCs unable to productively prime T cells, even in the presence of cognate peptide-MHC (Figure 3(B)) [47]. We have recently observed that infected murine DCs show impaired IS formation and fail to induce activation of T cells (Figures 2 and 3) [47]. Under our experimental settings, inhibition of T-cell activation required cell–cell contact and did not seem to depend on the secretion of soluble mediators by infected DCs, as it has been suggested by other studies (Figure 2) [47, 49, 53]. Therefore, inhibition of immunological synapse assembly by RSV is likely to involve molecules expressed by DCs during the infective cycle which are recruited to the DC–T cell interface (Figure 3(B)) [47]. This possibility is consistent with a study showing that human epithelial cells expressing the RSV fusion (F) protein inhibit T-cell activation [72], although this phenomenon has not been described yet for DCs. Further research is required to analyse the mechanisms responsible for the RSV inhibition of DC–T cell synapse assembly, as well as the biological function of other RSV proteins and their contribution to modulating the capacity of DCs to prime T cells.


Figure 3. Respiratory syncytial virus (RSV) impairs the establishment of the immunological synapse between DCs and T cells. (A) DC–T cell activating immunological synapses (IS) are characterized by cell–cell interfaces containing a peripheral ring harbouring adhesion molecules and an inner ring enriched in TCR–pMHC complexes, co-stimulatory molecules and activating cytokine receptors. Upon engagement with their ligands, these molecules can induce intracellular activating signals that accumulate and lead to T-cell activation and differentiation. (B) However, RSV-infected DCs express viral proteins that may be targeted to the DC–T cell interface, either intracellularly or at the cell surface. Such proteins could impair the localization and/or function of host activating molecules that are required for T-cell activation during IS assembly, progress and termination. In addition, RSV proteins may promote the recruitment of host molecules at the IS that inhibit T-cell activation. Activating and inhibitory cytokines secreted by RSV-infected DCs are likely to further modulate the signalling events taking place within T cells that are required for an adequate cell activation and differentiation. Taken together, the outcome of T-cell stimulation will depend on the integration of both activating and inhibitory stimuli provided by virus-infected DCs

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Additional factors participating during antigen presentation, such as the quantity of surface cognate peptide-MHC, the length of DC–T cell interactions and cytokines surrounding the DC–T cell environment can also influence the outcome of synapse assembly and efficiency and ultimately define the effector phenotype of the responding T cells [73-76]. Thus, the integration of activating and inhibitory signalling events in T cells, resulting from distinct stimuli and signalling pathways including TCR–peptide–MHC interaction, co-stimulatory molecules and cytokine receptors, will define the fate of antigen-specific T cells (Figure 3(B)). These observations emphasize that IS formation is a fine-tuned process that could be exploited at multiple levels either directly or indirectly by RSV virulence determinants to interfere with T-cell function. In fact, the diversity of T-cell phenotypes observed after exposure to RSV, such as pro-inflammatory phenotypes, Th2 commitment, partial T-cell activation or anergy, are in line with viral interference of DC–T cell IS (Figure 3(B)).

Another aspect related to the inhibition of T-cell function, although poorly explored, is the direct effect of RSV on these cells. Although viral proteins interact at the surface of T cells, replication of viral RNA is not observed within these cells, suggesting abortive infection [77]. However, providing RSV to human CD4+ T-cell cultures modulates the cytoskeleton and interferes with the activation of these cells by an unknown mechanism (Figure 2) [52]. These findings suggest that RSV could inhibit the function of non-antigen-specific T cells after infection, which is consistent with the observation that RSV suppresses the activation of bystander murine T cells in vivo as well as in vitro [38, 78].

Respiratory syncytial virus interferes with T-cell polarization

Although controversial [13], the severity of RSV infection in humans and animal models has been in part associated with the expansion of CD4+ T cells that display phenotypes that are non-optimal for virus clearance [39, 40, 79-81]. As part of this type of response, T cells recognizing RSV antigens often polarize towards a Th2 phenotype and secrete or promote the secretion of cytokines, such as IL-4, IL-5 and IL-13 [39, 40, 79, 80, 82-84]. These molecules can positively modulate the activation and recruitment of other immune cells, such as eosinophils, neutrophils and monocytes, into the lungs, which produce and secrete pro-inflammatory molecules contributing to pathology [85-87]. Concomitantly, cytokines such as IL-9 and IL-4 can modulate the immune response by dampening the activity of cytotoxic virus-specific CD8+ T cells (Figure 2) [21, 31, 37, 38, 88]. Contrarily, an increase in the number of Th1-polarized RSV-specific T cells in the lungs can reduce RSV replication and decrease T-cell-associated pro-inflammatory cytokines [21, 24]. Studies in animal models have shown that the natural establishment or induction of a balanced Th1 immunity with vaccination can considerably improve the host response to RSV infection [21, 24, 32]. These observations support the idea that pro-inflammatory responses and their associated cytokines are generally related to RSV-induced pathology. On the contrary, a properly balanced Th1/Th2 polarization is required for limiting virus replication in the infected tissue and reducing lung pathology. These findings have been confirmed by data obtained from vaccination and virus challenge studies in animal models for RSV [21, 89-92].

Although CD8+ cytotoxic T cells are usually considered to be advantageous for viral clearance because they correlate positively with protective immunity in mice successfully vaccinated against RSV, some reports suggest that naturally occurring CD8+ T cells specific to the virus may play detrimental roles during primary infection and secondary challenge with the virus [29, 93]. This possibility is supported by the observation that depletion of CD8+ T cells during primary and secondary infections can reduce the severity of RSV-induced disease in infected animals [29]. It is thought that these detrimental virus-specific occurring CD8+ T cells may be secreting damaging pro-inflammatory cytokines that promote lung damage, similar to CD8+ T cells induced upon RSV-enhanced allergic inflammation [94]. However, it is important to point out that pathological CD8+ T cells could be modulated by regulatory CD4+ T cells in such a way to reduce virus-induced illness without affecting viral clearance in the lungs [93, 95].

Because RSV modulates CD4+ T-cell polarization, it was initially thought that the virus might also promote the expansion of regulatory T cells (Tregs) to downmodulate the activity of virus-specific cytotoxic T cells [49]. However, mice depleted of CD25+FoxP3+ regulatory T cells prior to infection display increased levels of pro-inflammatory chemokines and cytokines in the lungs after infection as compared with their non-depleted counterparts [96]. Furthermore, animals depleted of CD4+FOXP3+CD25+ natural Tregs show delayed recovery, enhanced weight loss and increased numbers of activated natural killer cells, which are thought to be beneficial for virus clearance [97]. This effect could be mediated by IL-10 secreted by these cells, which was recently shown to prevent excessive chemokine production and pro-inflammatory cytokines in the lungs after RSV infection [93]. Moreover, in one of these studies, Tregs were shown to differentially modulate the activity of RSV-specific CD8+ T cells to dominant and subdominant viral antigens [96, 98]. These observations suggest that Tregs play a favourable role during RSV infection by downmodulating the production of pro-inflammatory cytokines that could contribute to decreasing lung inflammation and to shaping T-cell immunity against the virus. Whether Tregs participate during RSV infection in humans remains to be determined. However, the idea of expanding Tregs in infected individuals to decrease lung inflammation and promote effective antiviral CD8+ T-cell function seems to have some promising prospect.

Respiratory syncytial virus interferes with T-cell migration

In addition to modulating the polarization of T cells towards pro-inflammatory phenotypes, the RSV G glycoprotein can also alter T-cell migration into the lungs (Figure 2) [99, 100]. The amino acid sequence of this glycoprotein contains an immune system-related CX3C chemokine domain that modulates T-cell migration and homing to the lungs. It is thought that this domain binds to CX3CR1 expressed on T cells [101, 102]. Indeed, the CX3C motif of the RSV G protein has been suggested to be responsible for reducing the frequency of CX3CR1+CD4+ and CX3CR1+CD8+ T cells in the lungs of infected animals, as well as the frequency of IFN-γ-secreting CX3CR1+ RSV-specific T cells in this tissue (Figure 2) [102]. This process is likely to be mediated by the soluble form of the RSV G protein diffusing from the site of infection (Figure 1) [103].


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Current available therapies for respiratory syncytial virus

A strategy that has been approved and made commercially available to prevent RSV infection consists of the intravenous administration of a neutralizing humanized monoclonal antibody that inhibits the fusion capacity of the RSV F protein [104]. This approach is aimed at decreasing the probability of RSV infection, mainly in preterm and other susceptible infants. Along these lines are studies in mice showing that targeting the conserved domain within the RSV G protein, which harbours a CX3C-associated motif with monoclonal antibodies, can reduce both inflammation and virus titres in the lungs [18, 105, 106]. Consistent with this notion, these anti-RSV G protein antibodies are produced poorly after natural infection with RSV [16-18]. Combined with anti-RSV F neutralizing antibodies, monoclonal antibodies directed to the CX3C portion of the G protein could provide a more powerful method for preventing and treating RSV-associated pathology [18, 104]. Although monoclonal antibodies have been proven to be effective at reducing RSV infection, it is still somewhat controversial whether antibodies generated against this virus during natural infection protect or not [14-17]. In any case, antibodies directed against RSV are likely to form immune complexes with the virus, which may be captured by Fcγ receptors expressed on the surface of DCs and presented to T cells [16, 17, 107-110]. A recent report showed that RSV–antibody immune complexes captured by Fcγ receptors on the surface of murine and human DCs can modulate the activation of CD4+ and CD8+ T cells against RSV [27]. Furthermore, it was observed that the ratio of murine CD4+/CD8+ T cells, which may be linked to adequate antiviral immunity, depends on whether these antibodies are neutralizing or not [27]. These studies will contribute to understanding the relationship between antiviral antibodies and T cells, a question that has been poorly assessed for viruses in general.

On the other hand, replication of RSV in the lungs may be treated with ribavirin, an analogue of purine nucleotides. Ribavirin is thought to interfere with virus dissemination by promoting disruptive mutations [7]. However, clinical trials aimed at assessing the use of ribavirin against RSV have ultimately displayed insufficient power for determining whether RSV treatment with this drug is effective or cost-effective, so the drug is approved for use in preterm infants experiencing severe infection only in a few countries [7]. A newly developed strategy directed at inhibiting viral replication in the lungs is the administration of small interfering RNAs directed against RSV genes, such as the phosphoprotein gene P and nucleocapsid N for their degradation [111-113]. This later approach is currently under clinical evaluation [111].

Failure of an inactivated respiratory syncytial virus vaccine

Only a few years after the virus was identified, a formalin-inactivated RSV preparation (FI-RSV) was used in a field trial during the mid-1960s as an initial attempt to vaccinate against the virus [114]. Unfortunately, after natural infection with RSV, children that had received this formulation showed an exacerbated pulmonary disease and suffered more severe symptoms than unvaccinated children [114, 115]. Data explaining the failure of FI-RSV as a vaccine were obtained decades after intense research and suggested that the formalin-inactivated RSV administered prior to infection with the virus promoted immune polarization to an allergic-like response in the lungs, causing exacerbated disease [116]. In animal models of RSV infection, immunization with inactivated virus followed by challenge with infective RSV also induces massive eosinophil infiltration to the lungs [116-120]. In addition, immune complex deposition and complement activation has been observed in both mouse models and infected patients [117]. This is due to the establishment of unbalanced Th1–Th2 polarized responses, which are characterized by the secretion of pro-inflammatory cytokines that drive excessive infiltration of eosinophils and neutrophils into the lungs. Although modification of viral epitopes by formalin was initially thought to be responsible for the inadequate immune response displayed after immunization with FI-RSV [121], the development of low-affinity antibodies against this inactivated virus was recently suggested to contribute to the observed damaging immune response by impairing virus neutralization and thus efficient viral clearance [119].

Current vaccine development to prevent respiratory syncytial virus-induced damage

Although a few passive prophylactic strategies are currently available for preventing infection of high-risk groups with RSV, cost-effective vaccines are highly demanded by public health systems to reduce hospitalization rates and the economic burden produced by this virus [5]. After the FI-RSV failed to produce immune protection, several new strategies aiming at inducing active prophylaxis against RSV infection were tried [114]. Thus, a formulation conferring protective immunity against RSV with minimal immunopathogenesis has been the goal of researchers around the world. However, to date no vaccine strategy capable of inducing active and long-lasting immunity to prevent RSV infection has reached the public. Given that the immune response against RSV is pivotal in the pathology to this virus, prophylactic treatments aiming to modulate this response in neonates are likely to be the best approach for developing an efficient vaccine. Such a vaccine should prevent pro-inflammatory T-cell polarization induced by RSV and overcome inhibition of naïve virus-specific T cells upon infection. This can be achieved by activating T cells with DCs induced to secrete balanced Th1/Th2-polarizing cytokines that promote an efficient immune response against the virus. A traditional strategy that has worked for several pathogenic viruses and bacteria involves the development of attenuated strains displaying minimal pathogenicity that preserve sufficient immunogenicity. Such attenuated strains have the advantage of expressing most of the pathogen's antigens, while maintaining virulence traits from the parental strain, strong enough to alert the immune system [122, 123]. Using this strategy, attenuated RSV strains have been developed that are fully restricted for growth at body temperature and thus are safe [122]. Other RSV strains have been engineered to carry gene deletions or point mutations at key viral genes that encode immune-modulating regions, such as the attachment glycoprotein G [123]. Another approach involves the generation of recombinant RSV strains carrying host cytokines that promote Th1-type immune responses, such as IL-2 or GM-CSF, as a mechanism to deliver activating cytokines to the site of infection [90, 91]. Similarly, RSV genes have been engineered to be expressed as chimaeras in other viruses, such as vaccinia virus, Sendai virus, parainfluenza and adenoviruses, which is a novel strategy for delivering viral antigens against RSV [92, 124]. However, a possible disadvantage of these approaches is that they may display reduced safety or lack sufficient immunogenicity to establish protective immunity against RSV [124-126].

Alternatively, formulations consisting of recombinant protein subunits have been increasingly used for vaccine development. These formulations can be applied either alone or in combination with bacterium-derived or plant-derived adjuvants to increase viral antigen immunogenicity [89, 127]. Although this approach benefits from increased safety, they may show reduced immunogenicity or unbalanced immune polarization [99, 100, 128], so they have not been developed further into clinical phases [125].

Another approach that requires further evaluation is the use of recombinant attenuated bacteria expressing RSV antigens [21, 129-131]. Because bacteria express many pathogen-associated molecular patterns on their surface, they can induce strong Th1, Th2 or Th17 polarizing immune responses directed to the recombinant heterologous antigens that they express. Recently, our group has generated strains of Bacille Calmette Guérin (BCG, an attenuated strain of Mycobacterium bovis) expressing either the N or M2-1 RSV antigens (rBCG-RSV) that induce an immune response that protects against virus infection in a mouse model [21, 28]. Unlike other strategies, this approach intends mainly to produce virus-specific T cells and not antibodies to the virus. We observed that rBCG-RSV produced RSV-specific protective Th1 immunity characterized by IFN-γ-secreting T cells and simultaneously prevented the generation of T cells producing Th2-type cytokines [28]. Another advantage of this formulation is the capacity to prevent inflammation or cellular infiltration in the infected lungs [21]. Furthermore, rBCG-RSV-induced T-cell immunity led to undetectable viral loads in the airways of challenged animals [28]. These data suggest that T cells induced after rBCG-RSV immunization can confer immune protection against RSV and that these cells are refractory to the mechanisms used by the virus to downmodulate adaptive immunity [21]. Because BCG has been used worldwide for nearly a century as a routine vaccine against tuberculosis (more than four billion doses administered to humans since 1921,, with a good safety record in newborns, it is possible that this approach might lead to an affordable and efficient vaccine against RSV [21, 130].

Another study has used an attenuated Salmonella strain as a bacterial vector for the delivery of RSV antigens, which induces immunity in an animal model of infection [129]. Oral administration of this vaccine promoted a balanced Th1/Th2 immune response characterized by the expansion of RSV-specific antibodies and cytotoxic T cells, reducing lung viral loads in infected mice [129]. Although there are no data showing how such vaccines can affect DC function, the induction of protective immunity by recombinant bacteria expressing RSV antigens suggests that these formulations can modulate the immune response to produce virus-specific IFN-γ secreting T cells and thus should be considered as potentially affordable and effective alternatives for immunizing against RSV.

These animal immunization studies have provided compelling evidence for the feasibility of prophylactic priming with immunogenic formulations prior to RSV exposure that can elicit protective immunity capable of preventing infection and pathology by the virus [21, 89, 90, 92, 127, 132]. Moreover, even if RSV virulence mechanisms are aimed at interfering with the establishment of an effective primary immune response, if virus-specific T cells are efficiently activated and differentiated by adequately primed DCs prior to natural infection, they may then be able to override inhibiting signals provided by virus-infected cells. This provides hope for the development of new effective vaccines against this widely disseminated pathogen.


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Research throughout these past years has defined RSV as a virus capable of producing excessive inflammation in the lungs while simultaneously interfering with T-cell function by modulating the immunobiology of DCs. However, severe disease leading to hospitalization after RSV infection only occurs in a fraction of individuals who are particularly susceptible to developing severe lung pathology. Ultimately, this process may lead to the establishment of an immunopathogenic-like disease. The identification of host and viral determinants defining this higher susceptibility and severity of disease after infection remains elusive. However, host genetic factors are likely to play relevant roles during infection and, thus, identifying and associating these markers with increased susceptibility is fundamental for the design of useful prognosis kits intended to predict disease outcome. On the other hand, new immune components have recently been shown to participate during RSV-induced pathology, which could help to define what differentiates an efficient viral immune response from a pathologic one. In this regard, alteration of DC function by RSV is likely to be a key event at determining the nature and function of the T-cell response during infection. Accordingly, RSV has developed molecular strategies to interfere with the capacity of DCs to efficiently activate T cells, such as blocking DC–T cell IS assembly, although the mechanism by which this occurs is currently unknown. Furthermore, whether increased susceptibility to suffer severe pathology is mainly attributable to the DC–RSV interaction remains to be assessed. T-cell commitment after interaction with DCs will be defined in part by surrounding cytokines provided by the innate immune response. However, the question as to how these factors trigger detrimental T-cell immune responses, particularly in susceptible individuals, remains unanswered. Identifying the mechanisms by which these cytokines influence the outcome of T cells is crucial, as well as the signalling events taking place in T cells primed by RSV-infected cells.

Addressing these questions should shed light on the mechanisms used by the virus to impair T-cell function, providing tools for predicting the severity of RSV-induced pathology and contributing to the design of effective and safe vaccines that induce balanced and robust protective immunity against RSV.


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The authors are supported by grants FONDECYT nº 1070352, FONDECYT nº 1085281, FONDECYT nº 1100926, FONDECYT nº 3070018, FONDECYT nº 3100090, FONDECYT nº 11075060, FONDECYT nº 1100926, FONDEF D06I1008, SavinMuco-Path-INCO-CT-2006-032296 and Millennium Institute on Immunology and Immunotherapy. A. M. K. is a Chercheur Étranger D'Excellence, Chaire de la Région Pays de la Loire.


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  • 1
    Storey S. Respiratory syncytial virus market. Nature Reviews. Drug Discovery 2010; 9: 1516.
  • 2
    Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. American Journal of Diseases of Children 1986; 140: 543546.
  • 3
    Henderson FW, Collier AM, Clyde WA Jr, et al. Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. The New England Journal of Medicine 1979; 300: 530534.
  • 4
    Welliver RC. Review of epidemiology and clinical risk factors for severe respiratory syncytial virus (RSV) infection. Journal of Pediatrics 2003; 143: S112S117.
  • 5
    Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010; 375: 15451555.
  • 6
    van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nature Medicine 2001; 7: 719724.
  • 7
    Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database of Systematic Reviews 2007; 1: CD000181.
  • 8
    Murata Y. Respiratory syncytial virus infection in adults. Current Opinion in Pulmonary Medicine 2008; 14: 235240.
  • 9
    Martinez FD. Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood asthma. Pediatric Infectious Disease Journal 2003; 22: S76S82.
  • 10
    Eisenhut M. Extrapulmonary manifestations of severe RSV bronchiolitis. Lancet 2006; 368: 988.
  • 11
    Eisenhut M. Extrapulmonary manifestations of severe respiratory syncytial virus infection—a systematic review. Critical Care 2006; 10: R107.
  • 12
    Thorburn K, Hart CA. Think outside the box: extrapulmonary manifestations of severe respiratory syncytial virus infection. Critical Care 2006; 10: 159.
  • 13
    Le Nouen C, Hillyer P, Munir S, et al. Effects of human respiratory syncytial virus, metapneumovirus, parainfluenza virus 3 and influenza virus on CD4+ T cell activation by dendritic cells. PLoS One 2010; 5: e15017.
  • 14
    Kawasaki Y, Hosoya M, Katayose M, et al. Role of serum neutralizing antibody in reinfection of respiratory syncytial virus. Pediatrics International 2004; 46: 126129.
  • 15
    Hall CB, Walsh EE, Long CE, et al. Immunity to and frequency of reinfection with respiratory syncytial virus. Journal of Infectious Diseases 1991; 163: 693698.
  • 16
    Handforth J, Friedland JS, Sharland M. Basic epidemiology and immunopathology of RSV in children. Paediatric Respiratory Reviews 2000; 1: 210214.
  • 17
    Dakhama A, Vitalis TZ, Hegele RG. Persistence of respiratory syncytial virus (RSV) infection and development of RSV-specific IgG1 response in a guinea-pig model of acute bronchiolitis. European Respiratory Journal 1997; 10: 2026.
  • 18
    Collarini EJ, Lee FE, Foord O, et al. Potent high-affinity antibodies for treatment and prophylaxis of respiratory syncytial virus derived from B cells of infected patients. Journal of Immunology 2009; 183: 63386345.
  • 19
    Bukreyev A, Yang L, Fricke J, et al. The secreted form of respiratory syncytial virus G glycoprotein helps the virus evade antibody-mediated restriction of replication by acting as an antigen decoy and through effects on Fc receptor-bearing leukocytes. Journal of Virology 2008; 82: 1219112204.
  • 20
    Zhou J, Yang XQ, Fu Z, et al. Increased pathogenesis and inflammation of airways from respiratory syncytial virus infection in T cell deficient nude mice. Medical Microbiology and Immunology 2008; 197: 345351.
  • 21
    Bueno SM, Gonzalez PA, Cautivo KM, et al. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proceedings of the National Academy of Sciences of the United States of America 2008; 105: 2082220827.
  • 22
    Bueno SM, Gonzalez PA, Pacheco R, et al. Host immunity during RSV pathogenesis. International Immunopharmacology 2008; 8: 13201329.
  • 23
    Gonzalez PA, Bueno SM, Riedel CA, et al. Impairment of T cell immunity by the respiratory syncytial virus: targeting virulence mechanisms for therapy and prophylaxis. Current Medicinal Chemistry 2009; 16: 46094625.
  • 24
    Olson MR, Hartwig SM, Varga SM. The number of respiratory syncytial virus (RSV)-specific memory CD8 T cells in the lung is critical for their ability to inhibit RSV vaccine-enhanced pulmonary eosinophilia. Journal of Immunology 2008; 181: 79587968.
  • 25
    Graham BS, Bunton LA, Wright PF, et al. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. The Journal of Clinical Investigation 1991; 88: 10261033.
  • 26
    King JC Jr, Burke AR, Clemens JD, et al. Respiratory syncytial virus illnesses in human immunodeficiency virus- and noninfected children. The Pediatric Infectious Disease Journal 1993; 12: 733739.
  • 27
    Kruijsen D, Bakkers MJ, van Uden NO, et al. Serum antibodies critically affect virus-specific CD4(+)/CD8(+) T cell balance during respiratory syncytial virus infections. Journal of Immunology 2010; 185: 64896498.
  • 28
    Cautivo KM, Bueno SM, Cortes CM, et al. Efficient lung recruitment of respiratory syncytial virus-specific Th1 cells induced by recombinant Bacillus Calmette-Guerin promotes virus clearance and protects from infection. Journal of Immunology 2010; 185: 76337645.
  • 29
    Tregoning JS, Yamaguchi Y, Harker J, et al. The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice. Journal of Virology 2008; 82: 41154124.
  • 30
    Beckham JD, Cadena A, Lin J, et al. Respiratory viral infections in patients with chronic, obstructive pulmonary disease. Journal of Infection 2005; 50: 322330.
  • 31
    Chang J, Braciale TJ. Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract. Nature Medicine 2002; 8: 5460.
  • 32
    Chang J, Choi SY, Jin HT, et al. Improved effector activity and memory CD8 T cell development by IL-2 expression during experimental respiratory syncytial virus infection. Journal of Immunology 2004; 172: 503508.
  • 33
    Carreno LJ, Gonzalez PA, Bueno SM, et al. Modulation of the dendritic cell–T-cell synapse to promote pathogen immunity and prevent autoimmunity. Immunotherapy 2011; 3: 611.
  • 34
    Didierlaurent A, Goulding J, Patel S, et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. The Journal of Experimental Medicine 2008; 205: 323329.
  • 35
    Telcian AG, Laza-Stanca V, Edwards MR, et al. RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8+ T cell nonspecific antiviral activity. Journal of Infectious Diseases 2011; 203: 8594.
  • 36
    Tourdot S, Mathie S, Hussell T, et al. Respiratory syncytial virus infection provokes airway remodelling in allergen-exposed mice in absence of prior allergen sensitization. Clinical and Experimental Allergy 2008; 38: 10161024.
  • 37
    DiNapoli JM, Murphy BR, Collins PL, et al. Impairment of the CD8+ T cell response in lungs following infection with human respiratory syncytial virus is specific to the anatomical site rather than the virus, antigen, or route of infection. Virology Journal 2008; 5: 105.
  • 38
    Vallbracht S, Unsold H, Ehl S. Functional impairment of cytotoxic T cells in the lung airways following respiratory virus infections. European Journal of Immunology 2006; 36: 14341442.
  • 39
    Munir S, Hillyer P, Le Nouen C, et al. Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. PLoS Pathogens 2011; 7: e1001336.
  • 40
    Varga SM, Wang X, Welsh RM, et al. Immunopathology in RSV infection is mediated by a discrete oligoclonal subset of antigen-specific CD4(+) T cells. Immunity 2001; 15: 637646.
  • 41
    Bueno SM, Gonzalez PA, Carreno LJ, et al. The capacity of Salmonella to survive inside dendritic cells and prevent antigen presentation to T cells is host specific. Immunology 2008; 4: 522533.
  • 42
    Tobar JA, Carreno LJ, Bueno SM, et al. Virulent Salmonella enterica serovar Typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infection and Immunity 2006; 74: 64386448.
  • 43
    Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. Journal of Biochemistry 2007; 141: 137145.
  • 44
    Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Current Topics in Microbiology and Immunology 2006; 311: 1758.
  • 45
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: 245252.
  • 46
    Guerrero-Plata A, Casola A, Suarez G, et al. Differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus. American Journal of Respiratory Cell and Molecular Biology 2006; 34: 320329.
  • 47
    Gonzalez PA, Prado CE, Leiva ED, et al. Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 2008; 105: 1499915004.
  • 48
    Le Nouen C, Munir S, Losq S, et al. Infection and maturation of monocyte-derived human dendritic cells by human respiratory syncytial virus, human metapneumovirus, and human parainfluenza virus type 3. Virology 2009; 385: 169182.
  • 49
    de Graaff PM, de Jong EC, van Capel TM, et al. Respiratory syncytial virus infection of monocyte-derived dendritic cells decreases their capacity to activate CD4 T cells. Journal of Immunology 2005; 175: 59045911.
  • 50
    Johnson TR, Johnson CN, Corbett KS, et al. Primary human mDC1, mDC2, and pDC dendritic cells are differentially infected and activated by respiratory syncytial virus. PLoS One 2011; 6: e16458.
  • 51
    Boogaard I, van Oosten M, van Rijt LS, et al. Respiratory syncytial virus differentially activates murine myeloid and plasmacytoid dendritic cells. Immunology 2007; 122: 6572.
  • 52
    Rothoeft T, Fischer K, Zawatzki S, et al. Differential response of human naive and memory/effector T cells to dendritic cells infected by respiratory syncytial virus. Clinical and Experimental Immunology 2007; 150: 263273.
  • 53
    Chi B, Dickensheets HL, Spann KM, et al. Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus. Journal of Virology 2006; 80: 50325040.
  • 54
    Bartz H, Turkel O, Hoffjan S, et al. Respiratory syncytial virus decreases the capacity of myeloid dendritic cells to induce interferon-gamma in naive T cells. Immunology 2003; 109: 4957.
  • 55
    Thornburg NJ, Shepherd B, Crowe JE Jr. Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection. Journal of Virology 2010; 84: 1289512902.
  • 56
    Mukherjee S, Lindell DM, Berlin AA, et al. IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease. The American Journal of Pathology 2011; 179: 248258.
  • 57
    Moore ML, Newcomb DC, Parekh VV, et al. STAT1 negatively regulates lung basophil IL-4 expression induced by respiratory syncytial virus infection. Journal of Immunology 2009; 183: 20162026.
  • 58
    Lukens MV, Kruijsen D, Coenjaerts FE, et al. Respiratory syncytial virus-induced activation and migration of respiratory dendritic cells and subsequent antigen presentation in the lung-draining lymph node. Journal of Virology 2009; 83: 72357243.
  • 59
    Smit JJ, Lindell DM, Boon L, et al. The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections. PLoS One 2008; 3: e1720.
  • 60
    Gill MA, Palucka AK, Barton T, et al. Mobilization of plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. Journal of Infectious Diseases 2005; 1991: 11051115.
  • 61
    Wang H, Peters N, Laza-Stanca V, et al. Local CD11c+ MHC class II- precursors generate lung dendritic cells during respiratory viral infection, but are depleted in the process. Journal of Immunology 2006; 177: 25362542.
  • 62
    Guerrero-Plata A, Kolli D, Hong C, et al. Subversion of pulmonary dendritic cell function by paramyxovirus infections. Journal of Immunology 2009; 182: 307283.
  • 63
    Wang H, Peters N, Schwarze J. Plasmacytoid dendritic cells limit viral replication, pulmonary inflammation, and airway hyperresponsiveness in respiratory syncytial virus infection. Journal of Immunology 2006; 177: 62636270.
  • 64
    Smit JJ, Rudd BD, Lukacs NW. Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. The Journal of Experimental Medicine 2006; 203: 11531159.
  • 65
    Munir S, Le Nouen C, Luongo C, et al. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. Journal of Virology 2008; 82: 87808796.
  • 66
    Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. Journal of Virology 2005; 79: 53535362.
  • 67
    Elliott J, Lynch OT, Suessmuth Y, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin–Cullin E3 ligase. Journal of Virology 2007; 81: 34283436.
  • 68
    Jie Z, Dinwiddie DL, Senft AP, et al. Regulation of STAT signaling in mouse bone marrow derived dendritic cells by respiratory syncytial virus. Virus Research 2011; 156: 127133.
  • 69
    Kallal LE, Schaller MA, Lindell DM, et al. CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC. European Journal of Immunology 2010; 40: 10421052.
  • 70
    Dustin ML. T-cell activation through immunological synapses and kinapses. Immunological Reviews 2008; 221: 7789.
  • 71
    Carreno LJ, Riquelme EM, Gonzalez PA, et al. T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC. Proceedings of the National Academy of Sciences of the United States of America 2010; 107: 210215.
  • 72
    Schlender J, Walliser G, Fricke J, et al. Respiratory syncytial virus fusion protein mediates inhibition of mitogen-induced T-cell proliferation by contact. Journal of Virology 2002; 76: 11631170.
  • 73
    Maldonado RA, Irvine DJ, Schreiber R, et al. A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 2004; 431: 527532.
  • 74
    Rothoeft T, Gonschorek A, Bartz H, et al. Antigen dose, type of antigen-presenting cell and time of differentiation contribute to the T helper 1/T helper 2 polarization of naive T cells. Immunology 2003; 110: 430439.
  • 75
    Bromley SK, Peterson DA, Gunn MD, et al. Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation. Journal of Immunology 2000; 165: 1519.
  • 76
    Gonzalez PA, Carreno LJ, Figueroa CA, et al. Modulation of immunological synapse by membrane-bound and soluble ligands. Cytokine & Growth Factor Reviews 2007; 18: 1931.
  • 77
    Kauth M, Grage-Griebenow E, Rohde G, et al. Synergistically upregulated interleukin-10 production in cocultures of monocytes and T cells after stimulation with respiratory syncytial virus. International Archives of Allergy and Immunology 2007; 142: 116126.
  • 78
    Ostler T, Pircher H, Ehl S. “Bystander” recruitment of systemic memory T cells delays the immune response to respiratory virus infection. European Journal of Immunology 2003; 33: 18391848.
  • 79
    Sutton TC, Tayyari F, Khan MA, et al. T helper 1 background protects against airway hyperresponsiveness and inflammation in guinea pigs with persistent respiratory syncytial virus infection. Pediatric Research 2007; 61: 525529.
  • 80
    Monick MM, Powers LS, Hassan I, et al. Respiratory syncytial virus synergizes with Th2 cytokines to induce optimal levels of TARC/CCL17. Journal of Immunology 2007; 179: 16481658.
  • 81
    Byeon JH, Lee JC, Choi IS, et al. Comparison of cytokine responses in nasopharyngeal aspirates from children with viral lower respiratory tract infections. Acta Paediatrica 2009; 98: 725730.
  • 82
    Bermejo-Martin JF, Garcia-Arevalo MC, De Lejarazu RO, et al. Predominance of Th2 cytokines, CXC chemokines and innate immunity mediators at the mucosal level during severe respiratory syncytial virus infection in children. European Cytokine Network 2007; 18: 162167.
  • 83
    Shimojo N, Katsuki T, Tateno N, et al. T helper lymphocyte response to respiratory syncytial virus and its components in patients with respiratory allergy and nonatopic controls. International Archives of Allergy and Immunology 2008; 147: 110116.
  • 84
    Alwan WH, Kozlowska WJ, Openshaw PJ. Distinct types of lung disease caused by functional subsets of antiviral T cells. The Journal of Experimental Medicine 1994; 179: 8189.
  • 85
    Castilow EM, Meyerholz DK, Varga SM. IL-13 is required for eosinophil entry into the lung during respiratory syncytial virus vaccine-enhanced disease. Journal of Immunology 2008; 180: 23762384.
  • 86
    Fischer JE, Johnson JE, Kuli-Zade RK, et al. Overexpression of interleukin-4 delays virus clearance in mice infected with respiratory syncytial virus. Journal of Virology 1997; 71: 86728677.
  • 87
    Johnson TR, Rothenberg ME, Graham BS. Pulmonary eosinophilia requires interleukin-5, eotaxin-1, and CD4+T cells in mice immunized with respiratory syncytial virus G glycoprotein. Journal of Leukocyte Biology 2008; 84: 748759.
  • 88
    Dodd JS, Lum E, Goulding J, et al. IL-9 regulates pathology during primary and memory responses to respiratory syncytial virus infection. Journal of Immunology 2009; 183: 70067013.
  • 89
    Cyr SL, Jones T, Stoica-Popescu I, et al. Intranasal proteosome-based respiratory syncytial virus (RSV) vaccines protect BALB/c mice against challenge without eosinophilia or enhanced pathology. Vaccine 2007; 25: 53785389.
  • 90
    Bukreyev A, Belyakov IM, Berzofsky JA, et al. Granulocyte-macrophage colony-stimulating factor expressed by recombinant respiratory syncytial virus attenuates viral replication and increases the level of pulmonary antigen-presenting cells. Journal of Virology 2001; 75: 1212812140.
  • 91
    Bukreyev A, Whitehead SS, Prussin C, et al. Effect of coexpression of interleukin-2 by recombinant respiratory syncytial virus on virus replication, immunogenicity, and production of other cytokines. Journal of Virology 2000; 74: 71517157.
  • 92
    Voges B, Vallbracht S, Zimmer G, et al. Recombinant Sendai virus induces T cell immunity against respiratory syncytial virus that is protective in the absence of antibodies. Cellular Immunology 2007; 247: 8594.
  • 93
    Weiss KA, Christiaansen AF, Fulton RB, et al. Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. Journal of Immunology 2011; 187: 31453154.
  • 94
    Jiang XB, Wang ZD, Zhu Y, et al. Inhibition of CD8+ T lymphocytes attenuates respiratory syncytial virus-enhanced allergic inflammation. Respiration 2009; 77: 7684.
  • 95
    Liu J, Ruckwardt TJ, Chen M, et al. Epitope-specific regulatory CD4 T cells reduce virus-induced illness while preserving CD8 T-cell effector function at the site of infection. Journal of Virology 2010; 84: 1050110509.
  • 96
    Ruckwardt TJ, Bonaparte KL, Nason MC, et al. Regulatory T cells promote early influx of CD8+ T cells in the lungs of respiratory syncytial virus-infected mice and diminish immunodominance disparities. Journal of Virology 2009; 83: 30193028.
  • 97
    Lee DC, Harker JA, Tregoning JS, et al. CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection. Journal of Virology 2010; 84: 87908798.
  • 98
    Fulton RB, Meyerholz DK, Varga SM. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. Journal of Immunology 2010; 185: 23822392.
  • 99
    Hancock GE, Speelman DJ, Heers K, et al. Generation of atypical pulmonary inflammatory responses in BALB/c mice after immunization with the native attachment (G) glycoprotein of respiratory syncytial virus. Journal of Virology 1996; 70: 77837791.
  • 100
    Tebbey PW, Hagen M, Hancock GE. Atypical pulmonary eosinophilia is mediated by a specific amino acid sequence of the attachment (G) protein of respiratory syncytial virus. The Journal of Experimental Medicine 1998; 188: 19671972.
  • 101
    Tripp RA, Jones LP, Haynes LM, et al. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nature Immunology 2001; 2: 732738.
  • 102
    Harcourt J, Alvarez R, Jones LP, et al. Respiratory syncytial virus G protein and G protein CX3C motif adversely affect CX3CR1+ T cell responses. Journal of Immunology 2006; 176: 16001608.
  • 103
    Arnold R, Konig B, Werchau H, et al. Respiratory syncytial virus deficient in soluble G protein induced an increased proinflammatory response in human lung epithelial cells. Virology 2004; 330: 384397.
  • 104
    The_IMpact-RSV_Study_Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531537.
  • 105
    Haynes LM, Caidi H, Radu GU, et al. Therapeutic monoclonal antibody treatment targeting respiratory syncytial virus (RSV) G protein mediates viral clearance and reduces the pathogenesis of RSV infection in BALB/c mice. The Journal of Infectious Diseases 2009; 200: 439447.
  • 106
    Miao C, Radu GU, Caidi H, et al. Treatment with respiratory syncytial virus G glycoprotein monoclonal antibody or F(ab')2 components mediates reduced pulmonary inflammation in mice. The Journal of General Virology 2009; 90: 11191123.
  • 107
    Kalergis AM, Ravetch JV. Inducing tumor immunity through the selective engagement of activating Fcgamma receptors on dendritic cells. The Journal of Experimental Medicine 2002; 195: 16531659.
  • 108
    Herrada AA, Contreras FJ, Tobar JA, et al. Immune complex-induced enhancement of bacterial antigen presentation requires Fcgamma receptor III expression on dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 2007; 104: 1340213407.
  • 109
    Tobar JA, Gonzalez PA, Kalergis AM. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells. Journal of Immunology 2004; 173: 40584065.
  • 110
    Liu Y, Gao X, Masuda E, et al. Regulated expression of FcgammaR in human dendritic cells controls cross-presentation of antigen–antibody complexes. Journal of Immunology 2006; 177: 84408447.
  • 111
    DeVincenzo J, Lambkin-Williams R, Wilkinson T, et al. A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proceedings of the National Academy of Sciences of the United States of America 2010; 107: 88008805.
  • 112
    Zhang W, Tripp RA. RNA interference inhibits respiratory syncytial virus replication and disease pathogenesis without inhibiting priming of the memory immune response. Journal of Virology 2008; 82: 1222112231.
  • 113
    Bitko V, Musiyenko A, Shulyayeva O, et al. Inhibition of respiratory viruses by nasally administered siRNA. Nature Medicine 2005; 11: 5055.
  • 114
    Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. American Journal of Epidemiology 1969; 89: 422434.
  • 115
    Kapikian AZ, Mitchell RH, Chanock RM, et al. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. American Journal of Epidemiology 1969; 89: 405421.
  • 116
    Connors M, Kulkarni AB, Firestone CY, et al. Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells. Journal of Virology 1992; 66: 74447451.
  • 117
    Polack FP, Teng MN, Collins PL, et al. A role for immune complexes in enhanced respiratory syncytial virus disease. The Journal of Experimental Medicine 2002; 196: 859865.
  • 118
    Murphy BR, Sotnikov AV, Lawrence LA, et al. Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization. Vaccine 1990; 8: 497502.
  • 119
    Delgado MF, Coviello S, Monsalvo AC, et al. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nature Medicine 2009; 15: 3441.
  • 120
    Kruijsen D, Schijf MA, Lukens MV, et al. Local innate and adaptive immune responses regulate inflammatory cell influx into the lungs after vaccination with formalin inactivated RSV. Vaccine 2011; 29: 27302741.
  • 121
    Moghaddam A, Olszewska W, Wang B, et al. A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Nature Medicine 2006; 12: 905907.
  • 122
    Collins PL, Murphy BR. New generation live vaccines against human respiratory syncytial virus designed by reverse genetics. Proceedings of the American Thoracic Society 2005; 2: 166173.
  • 123
    Elliott MB, Pryharski KS, Yu Q, et al. Recombinant respiratory syncytial viruses lacking the C-terminal third of the attachment (G) protein are immunogenic and attenuated in vivo and in vitro. Journal of Virology 2004; 78: 57735783.
  • 124
    Collins PL, Purcell RH, London WT, et al. Evaluation in chimpanzees of vaccinia virus recombinants that express the surface glycoproteins of human respiratory syncytial virus. Vaccine 1990; 8: 164168.
  • 125
    Crowe JE Jr, Randolph V, Murphy BR. The live attenuated subgroup B respiratory syncytial virus vaccine candidate RSV 2B33F is attenuated and immunogenic in chimpanzees, but exhibits partial loss of the ts phenotype following replication in vivo. Virus Research 1999; 59: 1322.
  • 126
    Crowe JE Jr, Collins PL, London WT, et al. A comparison in chimpanzees of the immunogenicity and efficacy of live attenuated respiratory syncytial virus (RSV) temperature-sensitive mutant vaccines and vaccinia virus recombinants that express the surface glycoproteins of RSV. Vaccine 1993; 11: 13951404.
  • 127
    Etchart N, Baaten B, Andersen SR, et al. Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge. European Journal of Immunology 2006; 36: 11361144.
  • 128
    Huang Y, Cyr SL, Burt DS, et al. Murine host responses to respiratory syncytial virus (RSV) following intranasal administration of a Protollin-adjuvanted, epitope-enhanced recombinant G protein vaccine. Journal of Clinical Virology 2009; 44: 287291.
  • 129
    Xie C, He JS, Zhang M, et al. Oral respiratory syncytial virus (RSV) DNA vaccine expressing RSV F protein delivered by attenuated Salmonella Typhimurium. Human Gene Therapy 2007; 18: 746752.
  • 130
    Haas MJ, Besieging RSV. SciBX 2009; 2: 79.
  • 131
    Bueno SM, Gonzalez PA, Kalergis AM. Use of genetically modified bacteria to modulate adaptive immunity. Current Gene Therapy 2009; 9: 171184.
  • 132
    Zeng R, Zhang Z, Mei X, et al. Protective effect of a RSV subunit vaccine candidate G1F/M2 was enhanced by a HSP70-like protein in mice. Biochemical and Biophysical Research Communications 2008; 377: 495499.